Cyclopropyl amino acid analogues (cyclopropylogs) of the neuromodulatory peptides FMRF-NH2 and F-8-F-NH2 will be prepared. Literature on these substances indicates that their activity depends on an ArgPheNH2 C-terminus so initial efforts will be concentrated on this fragment. All four diastereomeric cyclopropylogs of Phe will be synthesized and incorporated into the Phe4 position of FMRF-NH2 and into the Phe8 position of F-8-F-NH2. These eight peptides will be tested for morphine agonist and antagonist activity. We shall also prepare the four diastereomeric cycopropylogs of Arg, incorporate them into FMRF-NH2 and F-8-F-NH2, and test these peptidomimetics in the same way. diastereomeric cyclopropylogs of the other amino acid constituents of these two peptides will also be prepared and substituted for their parent residues. A total of 48 single substitutions are possible, more than could be prepared and tested in the course of this proposal within the budget requested, consequently emphasis will be placed on substitutions near the crucial ArgPheNH2 residue. Conformational preferences of isolated molecules of the peptidomimetics (and their parent peptides) will be assessed by NMR and these results will be correlated with calculations made using QUANTA-CHARMm. Where possible, the solid state structure of the peptidomimetics will be determined using X-ray crystallography. These data will provide indications of the shape of the receptor surface(s) involved in molecular recognition of these neuromodulatory peptides and lay foundations for computer-assisted design and synthesis of molecules (not necessarily peptides) which may bind to reputed opiate antagonist receptor surfaces. In the long term, drugs which interact with the appropriate receptor surface(s) in the human brain but do not stimulate it (i.e. are not opiate antagonists) may be used to prevent tolerance and dependance to analgesics. Other compounds, artificial F-8-F- NH2 related antagonists, could be developed to alleviate the undesirable effects of withdrawal from morphine and related substances.